PROJECT SUMMARY Administration of estrogens begun during a critical window near menopause is hypothesized to prevent or delay age-associated cognitive decline and Alzheimer's disease and related dementias. However, due to potential health risks women often limit use of estrogen therapy to a few years to treat menopausal symptoms. The long-term consequences for the brain, cognitive aging, and risk of dementia of short-term use of estrogens are unknown. The long-term goal of the research is to determine the consequences for the female brain and for female cognitive aging of short-term exposure to estrogens during middle-age such as that used by women during the menopausal transition. The central hypothesis to be tested by the currently proposed studies is that in aging females, a history of previous midlife estradiol treatment decreases and exposure to stressful conditions increases degradation rate of ER? in the hippocampus, thereby affecting levels of ER? that are available to be activated via mechanisms involving neuroestrogens and IGF-1 to ultimately impact cognitive aging. Guided by supporting data, this hypothesis will be tested by three specific aims: 1) To identify mechanisms by which previous short-term estradiol exposure is able to have long-term impacts on protein degradation of ER? in the hippocampus; 2) To determine the role of brain-synthesized or neuroestrogens, acting both independently and via interactions with IGF-1, in the ability of short-term estradiol exposure to exert lasting impacts on the hippocampus and memory; and, 3) To determine the impact for cognition of the decrease in ER? expression in the hippocampus that results from exposure to stressful conditions in aging females with and without a history of previous estradiol treatment. Experiments under the first aim will use a rat model of midlife estradiol use and a) manipulate components of the ubiquitin-proteasomal protein degradation pathway to enhance or attenuate its activity and determine effects on the ability of previous estradiol exposure to impact ER? degradation; and b) assess the relationship between the ability of neuroestrogens and IGF-1 to phosphorylate ER? and their ability to impact its degradation. Experiments under the second aim will employ both a rat model of midlife estradiol use and a transgenic mouse model (ERE-Luciferase mice), which allows for direct measurement of ER-dependent transcription, and assess effects of pharmacological blockage of brain IGF-1 receptors, neuroestrogen synthesis, or both on measures of ER? activation and memory. Experiments under the third aim will expose aging ovariectomized rats with and without a history of previous estradiol treatment as well as aging males to repeated stress and determine a) impact on ubiquitination and degradation of ER?, and b) if manipulations that increase hippocampal ER? attenuate negative effects of stress on memory and the hippocampus. Completion of the proposed aims is expected to have a positive impact on the study of cognitive aging by providing elucidation of mechanisms by which factors that impact estrogen receptors in aging brains exert lasting impacts on cognition in the absence of ovarian or endogenously administered estrogens.